METAL-FREE SYNTHESIS of 2,3-DIHYDROQUINAZOLINONE DERIVATIVES USING 5-SULFOSALICYLIC ACID AS an ORGANOCATALYST Chandrakant D

Bhenki et al RJLBPCS 2020 www.rjlbpcs.com Life Science Informatics Publications Original Research Article DOI: 10.26479/2020.0602.04 METAL-FREE SYNTHESIS OF 2,3-DIHYDROQUINAZOLINONE DERIVATIVES USING 5-SULFOSALICYLIC ACID AS AN ORGANOCATALYST Chandrakant D. Bhenki1, 2*, Shrikrishna S. Karhale1, Kiran N. Patil3, Vasant B. Helavi1 1. Department of Chemistry, Rajaram College, Kolhapur, (M.S.), India. 2. Department of Chemistry, Shri S. H. Kelkar College, Devgad, Sindhudurg, (M.S.), India. 3. Department of Chemistry, Dr.Ghali College, Gadhinglaj, Kolhapur, (M.S.), India ABSTRACT: An efficient, selective and green protocol for the synthesis of 2,3- dihydroquinazolinone derivatives developed by the reaction of 2-aminobenzamide and aromatic aldehydes under metal-free conditions using 5-sulfosalicylic acid (5-SSA) as an organocatalyst in ethanol - water (1:1,v/v) system. The main advantages of this procedure include the use of an organocatalyst, practical simplicity, high yields, eco-friendly solvent, atom economy and ease of isolation of the product. Keywords: Organocatalyst, Metal-free synthesis, High atom economy,2,3-dihydroquinazolinones, Green protocol etc. Article History: Received: March 10, 2020; Revised: March 29, 2020; Accepted: April 15, 2020. Corresponding Author: Mr. Chandrakant D. Bhenki* Department of Chemistry, Shri S. H. Kelkar College, Devgad, Sindhudurg, Pin.: 416613, (M.S.), India, Email address: [email protected] 1.INTRODUCTION In several important natural and synthetic organic derivatives, the quinazolinone ring is observed.[1] It is a useful privileged scaffold for library design and drug discovery applications. [2] 2, 3-dihydroquinazolinone derivatives are reported as an anticancer, [3] antihypertensive agent.[4] 2, 3-dihydroquinazolinone derivatives having a broad range of potential biological and pharmacological activities,[5]as well as their importance in the preparation of drug molecules and natural product, therefore they becomes an important class of fused heterocycles.[6] Drugs having a quinazolinone ring are Diproqualone which is used as anti inflammatory and Methaqualone is © 2020 Life Science Informatics Publication All rights reserved Peer review under responsibility of Life Science Informatics Publications 2020 March – April RJLBPCS 6(2) Page No.52 Bhenki et al RJLBPCS 2020 www.rjlbpcs.com Life Science Informatics Publications used as antimalarial and currently being used for the assessment of the abuse liability of sedative - hypnotic drugs [7] as shown in Fig.1. O O N OH N OH N N Diproqualone Methaqualone Fig. 1. Biologically important scaffolds having quinazolinone skeleton. The increasing attention during the last decades for environmental protection has led both modern academic and industrial groups to develop less hazardous synthetic methodologies for organic synthesis. For the synthesis of biologically active organic molecules employing environmentally friendly organocatalyst has received much attention. Recently Hamzeh et al. found that the 5-SSA is used as a green catalyst for the synthesis of 1-amidoalkyl-2-naphthol by the reaction of 2- naphthol, substituted aldehyde and benzamide or acetamide. [8] Organocatalysts are simple organic molecules able to promote a wide range of chemical transformations.[9,10] They also typically have prominent characteristics including metal-free environment, relatively simple functionality, air stability, low cost, low toxicity and biological friendliness. [11,12] Search for more suitable preparation of 2,3-dihydroquinazolinone continues today. A particularly, catalyst suchasKAl(SO4)2.12H2O,[13]Fe3O4/Chitosen,[14]Al(H2PO4)3,[15]Zn(PFO)2,[16]SbCl3,[17](CeSO 4)2.4H2O,[18]SiCl4,[19]MWCNTS,[20]T3P,[21]Ionicliquid,[22]Tannicacid,[23]PEG400,[24]TBAB n ,[25]H-ZSM-5nanozeolite,[26]Fe3O4@SiO2-imid-PMA ,[27] etc. have been known to achieve this transformation. All these conventional methodologies have come across certain drawbacks such as transition metal catalyst, prolonged reaction times, tedious catalysts preparation and workup, use of toxic solvents. However the development of an efficient method , easy work up procedure, simple, environmentally benign protocol using a water soluble, metal-free catalyst and green solvent for the synthesis of quinazolinone derivatives is still desirable and in demand.[28] The development of organocatalyzed reactions in which the reactions are catalyzed by organic molecules is an important area for green synthesis. The use of water as the solvent increases the rate of the chemical reactions and also decreases the risk of organic solvent. Aqueous ethanol mixture for the reaction medium has worked wonderfully in many instances.[29] This offers a homogenous medium for many reactions and provides rate accelerations .[ 30] In continuation of our research in the development of environment-friendly methodologies for the synthesis of bioactive heterocyclic moieties. [31-34] In current work, we reported a novel methodology for the synthesis of 2,3-dihydroquinazolinone by ring closure of 2-aminobenzamide with substituted aromatic aldehydes, in the presence of 20 mol% 5-SSA in aqueous ethanol. To the best of our knowledge we develop this green methodology for the synthesis of an important class of fused heterocycles from cheap and easily available starting materials by employing cheap and easily © 2020 Life Science Informatics Publication All rights reserved Peer review under responsibility of Life Science Informatics Publications 2020 March – April RJLBPCS 6(2) Page No.53 Bhenki et al RJLBPCS 2020 www.rjlbpcs.com Life Science Informatics Publications available 5-SSA as an efficient organocatalyst in a green medium. 2. MATERIALS AND METHODS Experimental 5-sulfosalicylic acid (Spectrochem), 2-aminobenzamide (Thomas Baker), and aromatic aldehydes (Spectrochem and Thomas Baker) were used as received. All the reactions were carried out in dried glassware under an open atmosphere. The melting points of all purified synthesized compounds were recorded using a hot paraffin bath and are uncorrected. The IR spectra were recorded in the frequency range 500-4000 cm-1, on Alpha100508 FT-IR spectrometer. The NMR spectra were recorded on a Bruker Avance (400 MHz for 1H NMR and 100 MHz for 13C NMR) spectrometer using DMSO as solvent using Tetramethylsilane (TMS) as an internal standard. Chemical shifts (δ) are expressed in parts per million (ppm) values with the TMS as an internal reference, and coupling constants (J) are expressed in hertz (Hz). The Mass spectra of the purified product were recorded on a HRMS. General procedure for the synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives In 25 ml RB flask, a mixture of 2-aminobenzamide (1 mmol), aryl aldehyde (1 mmol), and 5- sulfosalicylic acid (20 mol%) in ethanol- water (1:1, v/v; 5 mL) was stirred at 80°C for a specified time (150 min – 240 min.) (Scheme 1 ) . Upon completion of the reaction as indicated by TLC, the reaction mixture was allowed to cool at room temperature and water (5 mL) was added and stirred continuously until solid was obtained in the reaction flask. The resultant solid was filtered, washed with water and then dried. The solid was recrystallized by pet ether: ethyl acetate (70:30, v/v). All the resulting products were pure and characterized by spectroscopic techniques. O O CHO NH NH 2 5-SSA (20mol%) + o N NH2 Ethanol:Water, 80 C R H R Scheme 1: Synthesis of 2,3-dihydroquinazolinone derivatives Spectral data of representative compounds 2-(4-nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (3b) (Table 3, entry 2) 1 Yellow Solis, Mp:198-199 °C, Yield = 92%, H NMR (400 MHz, CDCl3):δ = 6.74 - 6.76 (d, J = 8.4 Hz, 1 H), 8.22-8.25 (m, 1 H), 7.23-7.30(m, 2 H), 6.65-6.69 (m, 1 H), 5.89 (s, 1 H), 7.71- 13 7.74(d, J = 8.8 Hz, 1 H), 8.48 ( s, 1 H), 7.61 ( s, 1 H), CNMR (100 MHz, CDCl3): δ = 163.2, 149.2, 147.2, 147.1, 133.4, 127.3, 123.5, 177.4, 165.25. IR (KBr) cm–1: 3367, 3289, 3027, 1646, 1600, MS (ESI): m/z 270 [M +]. 2-(4-bromophenyl)-2,3-dihydroquinazolin-4(1H)-one (3c)( Table 3,entry 3) 1 Yellow Solid,Mp.196-197 °C, Yield =90%, H-NMR (400 MHz, CDCl3): δ = 7.56-7.25 (m, 5 H), 6.72-6.74 (d, J =8.0 Hz, 2 H), , 6.64-6.68 (m, 1 H), 5.74 (s, 1 H), 8.29 ( s, 1 H), 7.11, ( s, 1 H), 13C- © 2020 Life Science Informatics Publication All rights reserved Peer review under responsibility of Life Science Informatics Publications 2020 March – April RJLBPCS 6(2) Page No.54 Bhenki et al RJLBPCS 2020 www.rjlbpcs.com Life Science Informatics Publications NMR (100 MHz, CDCl3):δ=163.4, 147.5, 141.0, 133.3, 131.1, 129, 127.3, 121.4, 117.2, 114.4, 65.75, IR (KBr): 3367, 3282, 3038, 1647, 1603,MS (ESI): m/z 303 [M +]. 3. RESULTS AND DISCUSSION Initially, we chose a reaction of 2-aminobenzamide with 4-nitrobenzaldehyde as a model reaction in order to investigate the effects of solvent, temperature and amount of catalyst on the yield of the product.(Scheme 2) O CHO O NH 2 5-SSA, Ethanol:H2O NH NH + o 2 80 C N H NO2 NO2 Scheme 2: Synthesis of 2-(4-Nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (3b). For this purpose, we have screened several solvents such as toluene, THF, methanol, water, ethanol, acetonitrile, methylene dichloride, ethanol- water (1:1) etc. It was observed that the non- polar solvents such as toluene gave only moderate yields of the products (55%) and the polar solvents (ethanol, acetonitrile, methylene dichloride and methanol) give a much better yield than toluene, THF also gave a good yield for the reaction. In pursuance of making this protocol greener and economical, it was found that ethanol-water (1:1) acts more superior than other solvents, and gave excellent yield (92%) for this reaction (Table 1, Entry 3).

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